The focus of this project is to examine mechanisms of sympathetic activation and abnormal vascular function in obstructive sleep apnea (OSA). OSA has emerged as an important risk factor for hypertension, cardiovascular disease and premature death. Recent epidemiological and experimental data support the concept that OSA may cause hypertension. The mechanisms that link OSA and hypertension are unknown. Based on preliminary data, we postulate that increased activity of the sympathetic nervous system and an inability of peripheral blood vessels to vasodilate normally may contribute to the cardiovascular complications of OSA. Our prior investigations demonstrated that OSA is accompanied by chronic sympathoexcitation that is in part reversible with continuous positive airway pressure (CPAP) therapy. Conversely, preliminary data suggest that repetitive hypoxia leads to a sustained increase of sympathetic activity and blood pressure in normal humans. Preliminary data also suggest that the responses to chemoreflex stimulation are enhanced in OSA. Furthermore, based on preliminary data we postulate that in OSA the ability to vasodilate is impaired and that this vasodilator defect improves with CPAP therapy. The cause of impaired vasodilation in OSA is not known. In specific aim 1) we will determine the neurocirculatory effects of repetitive hypoxia in normal humans and in patients with OSA. We hypothesize that repetitive hypoxia leads to a sustained increase of sympathetic nerve activity and that these responses are accentuated in OSA. In specific aim 2) we will determine mechanisms responsible for impaired vasodilator capacity in OSA. We hypothesize that vasodilator capacity is reduced in OSA because of heightened sympathetic discharge and/or a specific vascular defect. If vasodilator function is restored after CPAP therapy, this will suggest that the repetitive hypoxic stress of OSA plays an important role. The studies will be performed in conscious humans in a General Clinical Research Center environment using state-of-the-art experimental techniques. Findings will provide insight into the link between OSA and cardiovascular disease and will increase our understanding of the interaction of sympathetic and vascular mechanisms in the regulation of blood flow and blood pressure.